Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

Ditte Demontis; Raymond K. Walters; Veera M. Rajagopal; Irwin D. Waldman; Jakob Grove; Thomas D. Als; Søren Dalsgaard; Marta Ribasas; Jonas Bybjerg-Grauholm; Maria Bækvad-Hansen; Thomas Werge; Merete Nordentoft; Ole Mors; Preben Bo Mortensen; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Bru Cormand; David M. Hougaard; Benjamin M. Neale; Barbara Franke; Stephen V. Faraone; Anders D. Børglum

doi:10.1038/s41467-020-20443-2

Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

Ditte Demontis, Raymond K. Walters, Veera M. Rajagopal, Irwin D. Waldman, Jakob Grove, Thomas D. Als, Søren Dalsgaard, Marta Ribasas, Jonas Bybjerg-Grauholm, Maria Bækvad-Hansen, Thomas Werge, Merete Nordentoft, Ole Mors, Preben Bo Mortensen, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Bru Cormand, David M. Hougaard, Benjamin M. Neale, Barbara Franke, Stephen V. FaraoneAnders D. Børglum

Psychology

Research output: Contribution to journal › Article › Research › peer-review

25 Citations (Scopus)

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10⁻¹⁰, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h²_SNP = 0.34) when compared to ADHD without DBDs (h²_SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (r_g = 0.81) and anti-social behaviors (r_g = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.

Original language	English
Article number	576
Number of pages	12
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20443-2
Publication status	Published - 25 Jan 2021

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Demontis, D., Walters, R. K., Rajagopal, V. M., Waldman, I. D., Grove, J., Als, T. D., Dalsgaard, S., Ribasas, M., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Werge, T., Nordentoft, M., Mors, O., Mortensen, P. B., ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Cormand, B., Hougaard, D. M., Neale, B. M., Franke, B., ... Børglum, A. D. (2021). Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder. Nature Communications, 12(1), Article 576. https://doi.org/10.1038/s41467-020-20443-2

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abstract = "Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10−10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.",

author = "Ditte Demontis and Walters, {Raymond K.} and Rajagopal, {Veera M.} and Waldman, {Irwin D.} and Jakob Grove and Als, {Thomas D.} and S{\o}ren Dalsgaard and Marta Ribasas and Jonas Bybjerg-Grauholm and Maria B{\ae}kvad-Hansen and Thomas Werge and Merete Nordentoft and Ole Mors and Mortensen, {Preben Bo} and Andreassen, {Ole A.} and Arranz, {Maria Jes{\'u}s} and Tobias Banaschewski and Claiton Bau and Mark Bellgrove and Joseph Biederman and Isabell Brikell and Buitelaar, {Jan K.} and Burton, {Christie L.} and Miguel Casas and Jennifer Crosbie and Doyle, {Alysa E.} and Ebstein, {Richard P.} and Josephine Elia and Elizabeth, {Corfield C.} and Eugenio Grevet and Natalie Grizenko and Alexandra Havdahl and Ziarih Hawi and Johannes Hebebrand and Amaia Hervas and Sarah Hohmann and Jan Haavik and Ridha Joober and Lindsey Kent and Jonna Kuntsi and Kate Langley and Henrik Larsson and Lesch, {Klaus Peter} and Leung, {Patrick W.L.} and Calwing Liao and Loo, {Sandra K.} and Joanna Martin and Martin, {Nicholas G.} and Medland, {Sarah E.} and Ana Miranda and Mota, {Nina Roth} and Oades, {Robert D.} and Ramos-Quiroga, {Josep Antoni} and Andreas Reif and Marcella Rietschel and Herbert Roeyers and Rohde, {Luis Augusto} and Aribert Rothenberger and Paula Rovira and Cristina S{\'a}nchez-Mora and Schachar, {Russell James} and Sarojini Sengupta and Artigas, {Maria Soler} and Steinhausen, {Hans Christoph} and Anita Thapar and Witt, {Stephanie H.} and Li Yang and Tetyana Zayats and Yanli Zhang-James and {ADHD Working Group of the Psychiatric Genomics Consortium (PGC)} and Bru Cormand and Hougaard, {David M.} and Neale, {Benjamin M.} and Barbara Franke and Faraone, {Stephen V.} and B{\o}rglum, {Anders D.}",

year = "2021",

month = jan,

day = "25",

doi = "10.1038/s41467-020-20443-2",

language = "English",

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Demontis, D, Walters, RK, Rajagopal, VM, Waldman, ID, Grove, J, Als, TD, Dalsgaard, S, Ribasas, M, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Werge, T, Nordentoft, M, Mors, O, Mortensen, PB, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Cormand, B, Hougaard, DM, Neale, BM, Franke, B, Faraone, SV & Børglum, AD 2021, 'Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder', Nature Communications, vol. 12, no. 1, 576. https://doi.org/10.1038/s41467-020-20443-2

TY - JOUR

T1 - Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

AU - Demontis, Ditte

AU - Walters, Raymond K.

AU - Rajagopal, Veera M.

AU - Waldman, Irwin D.

AU - Grove, Jakob

AU - Als, Thomas D.

AU - Dalsgaard, Søren

AU - Ribasas, Marta

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Maria

AU - Werge, Thomas

AU - Nordentoft, Merete

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Andreassen, Ole A.

AU - Arranz, Maria Jesús

AU - Banaschewski, Tobias

AU - Bau, Claiton

AU - Bellgrove, Mark

AU - Biederman, Joseph

AU - Brikell, Isabell

AU - Buitelaar, Jan K.

AU - Burton, Christie L.

AU - Casas, Miguel

AU - Crosbie, Jennifer

AU - Doyle, Alysa E.

AU - Ebstein, Richard P.

AU - Elia, Josephine

AU - Elizabeth, Corfield C.

AU - Grevet, Eugenio

AU - Grizenko, Natalie

AU - Havdahl, Alexandra

AU - Hawi, Ziarih

AU - Hebebrand, Johannes

AU - Hervas, Amaia

AU - Hohmann, Sarah

AU - Haavik, Jan

AU - Joober, Ridha

AU - Kent, Lindsey

AU - Kuntsi, Jonna

AU - Langley, Kate

AU - Larsson, Henrik

AU - Lesch, Klaus Peter

AU - Leung, Patrick W.L.

AU - Liao, Calwing

AU - Loo, Sandra K.

AU - Martin, Joanna

AU - Martin, Nicholas G.

AU - Medland, Sarah E.

AU - Miranda, Ana

AU - Mota, Nina Roth

AU - Oades, Robert D.

AU - Ramos-Quiroga, Josep Antoni

AU - Reif, Andreas

AU - Rietschel, Marcella

AU - Roeyers, Herbert

AU - Rohde, Luis Augusto

AU - Rothenberger, Aribert

AU - Rovira, Paula

AU - Sánchez-Mora, Cristina

AU - Schachar, Russell James

AU - Sengupta, Sarojini

AU - Artigas, Maria Soler

AU - Steinhausen, Hans Christoph

AU - Thapar, Anita

AU - Witt, Stephanie H.

AU - Yang, Li

AU - Zayats, Tetyana

AU - Zhang-James, Yanli

AU - ADHD Working Group of the Psychiatric Genomics Consortium (PGC)

AU - Cormand, Bru

AU - Hougaard, David M.

AU - Neale, Benjamin M.

AU - Franke, Barbara

AU - Faraone, Stephen V.

AU - Børglum, Anders D.

PY - 2021/1/25

Y1 - 2021/1/25

N2 - Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10−10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.

AB - Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10−10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.

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U2 - 10.1038/s41467-020-20443-2

DO - 10.1038/s41467-020-20443-2

M3 - Article

C2 - 33495439

AN - SCOPUS:85099802296

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 576

ER -

Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

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Author Correction: Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder (Nature Communications, (2021), 12, 1, (576), 10.1038/s41467-020-20443-2)

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